Implantable neurostimulator-implemented method for enhancing heart failure patient awakening through vagus nerve stimulation

ABSTRACT

An implantable neurostimulator-implemented method for managing tachyarrhythmias upon a patient&#39;s awakening from sleep through vagus nerve stimulation is provided. An implantable neurostimulator, including a pulse generator, is configured to deliver electrical therapeutic stimulation in a manner that results in creation and propagation (in both afferent and efferent directions) of action potentials within neuronal fibers comprising the cervical vagus nerve of a patient. Operating modes of the pulse generator are stored. An enhanced dose of the electrical therapeutic stimulation is parametrically defined and tuned to prevent initiation of or disrupt tachyarrhythmia upon the patient&#39;s awakening from a sleep state through at least one of continuously-cycling, intermittent and periodic ON-OFF cycles of electrical pulses. Other operating modes, including a maintenance dose and a restorative dose are defined. The patient&#39;s physiological state is monitored via at least one sensor to detect the patient&#39;s awakening, which activates the delivery of the enhanced dose.

CROSS REFERENCE TO RELATED APPLICATION

This patent application is a continuation of U.S. patent applicationSer. No. 13/673,811, filed Nov. 9, 2012, now U.S. Pat. No. 8,923,964,the priority of which is claimed and the disclosure of which isincorporated by reference in its entirety.

FIELD

This application relates in general to chronic cardiac dysfunctiontherapy and, in particular, to an implantableneurostimulator-implemented method for enhancing heart failure patientawakening through vagus nerve stimulation.

BACKGROUND

Congestive heart failure (CHF) and other forms of chronic cardiacdysfunction (CCD) are generally attributed to an autonomic imbalance ofthe sympathetic and parasympathetic nervous systems that, if leftuntreated, can lead to cardiac arrhythmogenesis, progressively worseningcardiac function and eventual patient death. CHF is pathologicallycharacterized by an elevated neuroexitatory state and is accompanied byphysiological indications of impaired arterial and cardiopulmonarybaroreflex function with reduced vagal activity.

CHF triggers compensatory activations of the sympathoadrenal(sympathetic) nervous system and the renin-angiotensin-aldosteronehormonal system, which initially help to compensate for deterioratingheart-pumping function, yet, over time, can promote progressive leftventricular dysfunction and deleterious cardiac remodeling. Patientssuffering from CHF are at increased risk of tachyarrhythmias, such asatrial fibrillation (AF), ventricular tachyarrhythmias (ventriculartachycardia (VT) and ventricular fibrillation (VF)), and atrial flutter,particularly when the underlying morbidity is a form of coronary arterydisease, cardiomyopathy, mitral valve prolapse, or other valvular heartdisease. Sympathoadrenal activation also significantly increases therisk and severity of tachyarrhythmias due to neuronal action of thesympathetic nerve fibers in, on, or around the heart and through therelease of epinephrine (adrenaline), which can exacerbate analready-elevated heart rate.

The increased risk of tachyarrhythmias, particularly VT, in CHF patientsis seen during the three-hour period following awakening from sleep,which is accompanied by a 2.5 times higher incidence of mortality.Tachyarrhythmias during awakening have been linked to a sympatheticactivity surge that naturally occurs whenever a person is waking up as apart of the natural human circadian rhythm cycle. Sleep is characterizedby the predominance of the parasympathetic system and a withdrawal ofsympathetic activity, followed by a peak of sympathetic activity upon aperson assuming an upright position and increasing activity level uponawakening. The surge of sympathetic activity increases heart rate, whichin turn makes a CHF patient more vulnerable to the development oftachyarrhythmias that can degenerate into a life-threatening VF episode.

Other forms of non-sleep related tachycardia, specificallysupraventricular (SVT), are relatively benign unless episodic orprolonged. In a patient with compromised cardiac function, though, anyform of tachyarrhythmia carries the potential of degrading into alife-threatening condition. Despite these increased risks, the currentstandard of care for treating CCD patients still relies on palliativepatient management, which recognizes the risk of tachyarrhythmiasoccurring upon patient awakening as an unavoidable side effect ofnatural circadian rhythm without specific care guidelines to lessen therisk.

The standard of care for managing CCD in general continues to evolve.For instance, new therapeutic approaches that employ electricalstimulation of neural structures that directly address the underlyingcardiac autonomic nervous system imbalance and dysregulation have beenproposed. In one form, controlled stimulation of the cervical vagusnerve beneficially modulates cardiovascular regulatory function.Currently, vagus nerve stimulation (VNS) is only approved for theclinical treatment of drug-refractory epilepsy and depression, althoughVNS has been proposed as a therapeutic treatment of CHF in general andhas been demonstrated in canine studies as efficacious in simulatedtreatment of AF and heart failure, such as described in Zhang et al.,“Therapeutic Effects of Selective Atrioventricular Node VagalStimulation in Atrial Fibrillation and Heart Failure,” J. Cardiovasc.Electrophysiol., Vol. pp. 1-6 (Jul. 9, 2012), the disclosure of which isincorporated by reference.

Conventional general therapeutic alteration of cardiac vagal efferentactivation through electrical stimulation targets only the efferentnerves of the parasympathetic nervous system, such as described inSabbah et al., “Vagus Nerve Stimulation in Experimental Heart Failure,”Heart Fail. Rev., 16:171-178 (2011), the disclosure of which isincorporated by reference. The Sabbah paper discusses canine studiesusing a vagus nerve stimulation system, manufactured by BioControlMedical Ltd., Yehud, Israel, which includes an electrical pulsegenerator, right ventricular endocardial sensing lead, and right vagusnerve cuff stimulation lead. The sensing lead enables stimulation of theright vagus nerve in a highly specific manner, which involvesclosed-loop synchronization of the vagus nerve stimulation pulse to thecardiac cycle. An asymmetric tri-polar nerve cuff electrode is implantedon the right vagus nerve at the mid-cervical position. The electrodeprovides cathodic induction of action potentials while simultaneouslyapplying asymmetric anodal blocks that lead to preferential activationof vagal efferent fibers. Electrical stimulation of the right cervicalvagus nerve is delivered only when heart rate increases beyond a presetthreshold. Stimulation is provided at an impulse rate and intensityintended to reduce basal heart rate by ten percent by preferentialstimulation of efferent vagus nerve fibers leading to the heart whileblocking afferent neural impulses to the brain. Although effective inpartially restoring baroreflex sensitivity and, in the canine model,increasing left ventricular ejection fraction and decreasing leftventricular end diastolic and end systolic volumes, the degree oftherapeutic effect on parasympathetic activation occurs throughincidental recruitment of afferent parasympathetic nerve fibers in thevagus, as well as through recruitment of efferent fibers. Efferentstimulation alone is less effective at restoring autonomic balance thanbi-directional stimulation.

Other uses of electrical nerve stimulation for therapeutic treatment ofvarious cardiac and physiological conditions are described. Forinstance, U.S. Pat. No. 6,600,954, issued Jul. 29, 2003 to Cohen et al.discloses a method and apparatus for selective control of nerve fiberactivations. An electrode device is applied to a nerve bundle capable ofgenerating, upon activation, unidirectional action potentials thatpropagate through both small diameter and large diameter sensory fibersin the nerve bundle, and away from the central nervous system. Thedevice is particularly useful for reducing pain sensations in the legsand arms.

U.S. Pat. No. 6,684,105, issued Jan. 27, 2004 to Cohen et al. disclosesan apparatus for treatment of disorders by unidirectional nervestimulation. An apparatus for treating a specific condition includes aset of one or more electrode devices that are applied to selected sitesof the central or peripheral nervous system of the patient. For someapplications, a signal is applied to a nerve, such as the vagus nerve,to stimulate efferent fibers and treat motility disorders, or to aportion of the vagus nerve innervating the stomach to produce asensation of satiety or hunger. For other applications, a signal isapplied to the vagus nerve to modulate electrical activity in the brainand rouse a comatose patient, or to treat epilepsy and involuntarymovement disorders.

U.S. Pat. No. 7,123,961, issued Oct. 17, 2006 to Kroll et al. disclosesstimulation of autonomic nerves. An autonomic nerve is stimulated toaffect cardiac function using a stimulation device in electricalcommunication with the heart by way of three leads suitable fordelivering multi-chamber stimulation and shock therapy. For arrhythmiadetection, the device utilizes atrial and ventricular sensing circuitsto sense cardiac signals to determine whether a rhythm is physiologic orpathologic. The timing intervals between sensed events are classified bycomparing them to a predefined rate zone limit and other characteristicsto determine the type of remedial therapy needed, which includesbradycardia pacing, anti-tachycardia pacing, cardioversion shocks(synchronized with an R-wave), or defibrillation shocks (deliveredasynchronously).

U.S. Pat. No. 7,225,017, issued May 29, 2007 to Shelchuk disclosesterminating ventricular tachycardia in connection with any stimulationdevice that is configured or configurable to stimulate nerves, orstimulate and shock a patient's heart. Parasympathetic stimulation isused to augment anti-tachycardia pacing, cardioversion, ordefibrillation therapy. To sense atrial or ventricular cardiac signalsand provide chamber pacing therapy, particularly on the left side of thepatient's heart, the stimulation device is coupled to a lead designedfor placement in the coronary sinus or its tributary veins.Cardioversion stimulation is delivered to a parasympathetic pathway upondetecting a ventricular tachycardia. A stimulation pulse is deliveredvia the lead to one or more electrodes positioned proximate to theparasympathetic pathway according to stimulation pulse parameters basedat least in part on the probability of reinitiation of an arrhythmia.

U.S. Pat. No. 7,277,761, issued Oct. 2, 2007 to Shelchuk discloses vagalstimulation for improving cardiac function in heart failure or CHFpatients. An autonomic nerve is stimulated to affect cardiac functionusing a stimulation device in electrical communication with the heart byway of three leads suitable for delivering multi-chamber endocardialstimulation and shock therapy. Where the stimulation device is intendedto operate as an implantable cardioverter-defibrillator (ICD), thedevice detects the occurrence of an arrhythmia, and automaticallyapplies an appropriate therapy to the heart aimed at terminating thedetected arrhythmia. Defibrillation shocks are generally of moderate tohigh energy level, delivered asynchronously, and pertaining exclusivelyto the treatment of fibrillation.

U.S. Pat. No. 7,295,881, issued Nov. 13, 2007 to Cohen et al. disclosesnerve branch-specific action potential activation, inhibition andmonitoring. Two preferably unidirectional electrode configurations flanka nerve junction from which a preselected nerve branch issues,proximally and distally to the junction, with respect to the brain.Selective nerve branch stimulation can be used in conjunction withnerve-branch specific stimulation to achieve selective stimulation of aspecific range of fiber diameters, substantially restricted to apreselected nerve branch, including heart rate control, where activatingonly the vagal B nerve fibers in the heart, and not vagal A nerve fibersthat innervate other muscles, can be desirous.

U.S. Pat. No. 7,778,703, issued Aug. 17, 2010 to Gross et al. disclosesselective nerve fiber stimulation for treating heart conditions. Anelectrode device is adapted to be coupled to a vagus nerve of a subjectand a control unit drives the electrode device by applying stimulatingand inhibiting currents to the vagus nerve, which are capable ofrespectively inducing action potentials in a therapeutic direction in afirst set and a second set of nerve fibers in the vagus nerve andinhibiting action potentials in the therapeutic direction in the secondset of nerve fibers only. The nerve fibers in the second set have largerdiameters than the nerve fibers in the first set. Typically, the systemis configured to treat heart failure or heart arrhythmia, such as atrialfibrillation or tachycardia by slowing or stabilizing the heart rate, orreducing cardiac contractility.

U.S. Pat. No. 7,813,805, issued Oct. 12, 2010 to Farazi and U.S. Pat.No. 7,869,869, issued Jan. 11, 2011 to Farazi both disclose subcardiacthreshold vagus nerve stimulation. A vagus nerve stimulator isconfigured to generate electrical pulses below a cardiac threshold,which are transmitted to a vagus nerve, so as to inhibit or reduceinjury resulting from ischemia. For arrhythmia detection, a heartstimulator utilizes atrial and ventricular sensing circuits to sensecardiac signals to determine whether a rhythm is physiologic orpathologic. In low-energy cardioversion, an ICD device typicallydelivers a cardioversion stimulus synchronously with a QRS complex;thus, avoiding the vulnerable period of the T-wave and avoiding anincreased risk of initiation of VF. In general, if anti-tachycardiapacing or cardioversion fails to terminate a tachycardia, then, forexample, after a programmed time interval or if the tachycardiaaccelerates, the ICD device initiates defibrillation therapy.

Finally, U.S. Pat. No. 7,885,709, issued Feb. 8, 2011 to Ben-Daviddiscloses nerve stimulation for treating disorders. A control unitdrives an electrode device to stimulate the vagus nerve, so as to modifyheart rate variability, or to reduce heart rate, by suppressing theadrenergic (sympathetic) system. Typically, the system is configured totreat heart failure or heart arrhythmia, such as atrial fibrillation ortachycardia. In one embodiment, a control unit is configured to drive anelectrode device to stimulate the vagus nerve, so as to modify heartrate variability to treat a condition of the subject. Therapeuticeffects of reduction in heart rate variability include the narrowing ofthe heart rate range, thereby eliminating very slow heart rates and veryfast heart rates. For this therapeutic application, the control unit istypically configured to reduce low-frequency heart rate variability, andto adjust the level of stimulation applied based on the circadian andactivity cycles of the subject. Therapeutic effects also includemaximizing the mechanical efficiency of the heart by maintainingrelatively constant ventricular filling times and pressures. Forexample, this therapeutic effect may be beneficial for subjectssuffering from atrial fibrillation, in which fluctuations in heartfilling times and pressure reduce cardiac efficiency.

Accordingly, a need remains for an approach to amelioratetachyarrhythmic risk in a heart failure patient during awakening.

SUMMARY

Excessive sustained activation of the sympathetic nervous system has adeleterious effect on long-term cardiac performance and increases therisk of tachyarrhythmias during awakening. In general, bi-directionalafferent and efferent neural stimulation through the vagus nerve canbeneficially restore autonomic balance and improve long term clinicaloutcome. Upon sensing a patient's awakening, VNS can be deliveredtherapeutically through an implantable vagus neurostimulator andelectrode lead to a patient in an enhanced dose for a fixed period oftime, absent arrhythmogenesis. Upon the expiration of the fixed period,other VNS doses can be engaged, such as a maintenance dose, if notachyarrhythmia is present, and a restorative dose, which is deliveredwhen the patient experiences a tachyarrhythmic event.

One embodiment provides an implantable neurostimulator-implementedmethod for managing tachyarrhythmias through vagus nerve stimulation. Animplantable neurostimulator, including a pulse generator, is configuredto deliver electrical therapeutic stimulation in a manner that resultsin creation and propagation (in both afferent and efferent directions)of action potentials within neuronal fibers comprising the cervicalvagus nerve of a patient. Operating modes are stored in the pulsegenerator. An enhanced dose of the electrical therapeutic current isparametrically defined and tuned to prevent initiation of or disrupttachyarrhythmia upon the patient's awakening from a sleep state throughat least one of continuously-cycling, intermittent and periodicelectrical pulses. A maintenance dose of the electrical therapeuticstimulation is parametrically defined and tuned to restore cardiacautonomic balance through continuously-cycling, intermittent andperiodic electrical pulses to be delivered at a lower intensity, whichcould be a lower output current, lower duty cycle, lower frequency, orshorter pulse width, than the enhanced dose. A restorative dose of theelectrical therapeutic stimulation is parametrically defined and tunedto prevent initiation of or disrupt tachyarrhythmia through periodicelectrical pulses delivered at higher intensity, which could be higheroutput current, higher duty cycle, higher frequency, or longer pulsewidth, than the maintenance dose. The patient's physiological state ismonitored using at least one sensor, such as an accelerometer to sensethe patient's posture and movements, a minute ventilation sensor tomonitor the patient's respiration, and a heart rate sensor to monitorthe patient's heart rate. The patient's normative physiology ismonitored via a physiological sensor included in the implantableneurostimulator, and upon sensing a condition indicative oftachyarrhythmia, the intensity of the enhanced dose can be increased.The increase can be progressive based on the patient's heart ratetrajectory, with the intensity increasing multiple times as thetachyarrhythmia fails to respond to the VNS stimulation or the deliveryof the enhanced dose can be maximized based on the patient's heart ratetrajectory. If the physiological sensors detect a condition indicativeof bradyarrhythmia, the enhanced dose is suspended. Upon an expirationof the period of time for delivery of the enhanced dose, the maintenancedose can be delivered if the patient is not experiencing atachyarrhythmic episode at the moment. If the patient is experiencingtachyarrhythmia at the time the period for delivery ends, therestorative dose can be delivered.

By improving autonomic balance and cardiovascular regulatory function,therapeutic VNS operates acutely to decrease heart rate, reflexivelyincrease heart rate variability and coronary flow, reduce cardiacworkload through vasodilation, and improve left ventricular relaxationwithout aggravating comorbid tachyarrhythmia or other cardiac arrhythmicconditions. Over the long term, low dosage VNS provides the chronicbenefits of decreased negative cytokine production, increased baroreflexsensitivity, increased respiratory gas exchange efficiency, favorablegene expression, renin-angiotensin-aldosterone system down-regulation,and anti-arrhythmic, anti-apoptotic, and ectopy-reducinganti-inflammatory effects. In short term, the delivery of the enhanceddose following the patient's awakening helps decrease the risk of havinga sudden cardiac death due to a diurnal peak in VT.

Still other embodiments of the present invention will become readilyapparent to those skilled in the art from the following detaileddescription, wherein are described embodiments by way of illustratingthe best mode contemplated for carrying out the invention. As will berealized, the invention is capable of other and different embodimentsand its several details are capable of modifications in various obviousrespects, all without departing from the spirit and the scope of thepresent invention. Accordingly, the drawings and detailed descriptionare to be regarded as illustrative in nature and not as restrictive.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a front anatomical diagram showing, by way of example,placement of an implantable vagus stimulation device in a male patient,in accordance with one embodiment.

FIGS. 2A and 2B are diagrams respectively showing the implantableneurostimulator and the simulation therapy lead of FIG. 1.

FIG. 3 is a graph showing, by way of example, the relationship betweenthe targeted therapeutic efficacy and the extent of potential sideeffects resulting from use of the implantable neurostimulator of FIG. 1.

FIG. 4 is a graph showing, by way of example, the optimal duty cyclerange based on the intersection depicted in FIG. 3.

FIG. 5 is a timing diagram showing, by way of example, a stimulationcycle and an inhibition cycle of VNS as provided by implantableneurostimulator of FIG. 1.

FIG. 6 is a flow diagram showing an implantableneurostimulator-implemented method for managing tachyarrhythmias uponawakening through vagus nerve stimulation, in accordance with oneembodiment.

FIG. 7 is a flow diagram showing a routine for delivering an enhanceddose of VNS stimulation upon the patient's awakening for use with themethod of FIG. 6, in accordance with one embodiment.

FIG. 8 is a flow diagram showing a routine for storing operating modesfor use with the method of FIG. 6.

DETAILED DESCRIPTION

Changes in autonomic control of the cardiovascular systems of patientssuffering from CHF and other cardiovascular diseases push the autonomicnervous system out of balance and favor increased sympathetic anddecreased parasympathetic central outflow. The imbalance is accompaniedby pronounced elevation of basal heart rate arising from chronicsympathetic hyperactivation along the neurocardiac axis, which isexacerbated during awakening by the surge in sympathetic activity thatis a part of natural human circadian rhythms.

Peripheral neurostimulation therapies that target the imbalance of theautonomic nervous system have been shown to improve clinical outcomes inpatients treated for three to twelve months. Specifically,bi-directional autonomic regulation therapy results in simultaneouscreation and propagation of efferent and afferent action potentialswithin afferent and efferent nerve fibers comprising the vagus nerve.The therapy directly restores autonomic balance by engaging bothmedullary and cardiovascular reflex control components of the autonomicnervous system. Upon stimulation of the cervical vagus nerve, actionpotentials propagate away from the stimulation site in two directions,efferently toward the heart and afferently toward the brain. Efferentaction potentials influence the intrinsic cardiac nervous system and theheart, while afferent action potentials influence central elements ofthe nervous system.

An implantable vagus nerve stimulator with integrated heart rate sensor,such as used to treat drug-refractory epilepsy and depression, can beadapted for use in managing chronic cardiac dysfunction during patientawakening through therapeutic bi-directional vagal stimulation. FIG. 1is a front anatomical diagram showing, by way of example, placement ofan implantable vagus nerve stimulation (VNS) device 11 in a male patient10, in accordance with one embodiment. The VNS provided through thestimulation device 11 operates under several mechanisms of action. Thesemechanisms include increasing parasympathetic outflow and inhibitingsympathetic effects by blocking norepinephrine release. Moreimportantly, VNS triggers the release of acetylcholine (ACh) into thesynaptic cleft, which has beneficial anti-arrhythmic, anti-apoptotic,and ectopy-reducing anti-inflammatory effects.

The implantable vagus stimulation device 11 includes at least threeimplanted components, an implantable neurostimulator 12, a therapy lead13, and helical electrodes 14. The implantable vagus stimulation device11 can be remotely accessed following implant through an externalprogrammer by which the neurostimulator 12 can be remotely checked andprogrammed by healthcare professionals; an external magnet, such asdescribed in commonly-assigned U.S. Pat. No. 8,600,505, entitled“Implantable Device For Facilitating Control Of Electrical StimulationOf Cervical Vagus Nerves For Treatment Of Chronic Cardiac Dysfunction,”Ser. No. 13/314,130, filed on Dec. 7, 2011, the disclosure of which isincorporated by reference, for basic patient control; and anelectromagnetic controller, such as described in commonly-assigned U.S.Pat. No. 8,571,654, entitled “Vagus Nerve Neurostimulator With MultiplePatient-Selectable Modes For Treating Chronic Cardiac Dysfunction,” Ser.No. 13/352,244, filed on Jan. 17, 2012, the disclosure of which isincorporated by reference, that enables the patient 10 to exerciseincreased control over therapy delivery and suspension. Together, theimplantable vagus stimulation device 11 and one or more of the externalcomponents form a VNS therapeutic delivery system.

The neurostimulator 12 is implanted in the patient's right or leftpectoral region generally on the same side (ipsilateral) as the vagusnerve 15, 16 to be stimulated, although other neurostimulator-vagusnerve configurations, including contra-lateral and bi-lateral arepossible. The helical electrodes 14 are generally implanted on the vagusnerve 15, 16 about halfway between the clavicle 19 a-b and the mastoidprocess. The therapy lead 13 and helical electrodes 14 are implanted byfirst exposing the carotid sheath and chosen vagus nerve 15, 16 througha latero-cervical incision on the ipsilateral side of the patient's neck18. The helical electrodes 14 are then placed onto the exposed nervesheath and tethered. A subcutaneous tunnel is formed between therespective implantation sites of the neurostimulator 12 and helicalelectrodes 14, through which the therapy lead 13 is guided to theneurostimulator 12 and securely connected.

In one embodiment, the stimulation device 11 delivers VNS while thepatient 10 is awake. The stimulation device 11 bi-directionallystimulates the vagus nerve 15, 16 through multimodal application ofcontinuously-cycling, intermittent and periodic electrical stimuli,which are parametrically defined through stored stimulation parametersand timing cycles. Upon patient awakening, an enhanced dose of VNS isdelivered to counter the increased tachyarrhythmic risk caused by thenatural circadian rhythm-triggered surge of sympathetic activity andincreased heart rate. In a further embodiment, tachyarrhythmias outsideof awakening can be managed through application of a restorative dose ofVNS upon the sensing of a condition indicative of tachyarrhythmias, suchas described in commonly-assigned U.S. patent application, entitled“Implantable Neurostimulator-Implemented Method for ManagingTachyarrhythmias through Vagus Nerve Stimulation,” Ser. No. 13/673,766,filed on Nov. 9, 2012, published as US 2014/0135862 A1, pending, thedisclosure of which is incorporated by reference. In a still furtherembodiment, bradycardia in VNS-titrated patients can be managed throughsuspension of on-going low-level VNS, such as described incommonly-assigned U.S. Pat. No. 8,688,212, entitled “ImplantableNeurostimulator-Implemented Method for Managing Bradycardia throughVagus Nerve Stimulation,” Ser. No. 13/554,656, filed on Jul. 20, 2012,the disclosure of which is incorporated by reference.

Both sympathetic and parasympathetic nerve fibers are stimulated.Cervical vagus nerve stimulation results in propagation of actionpotentials from the site of stimulation in a manner that results increation and propagation (in both afferent and efferent directions) ofaction potentials within neuronal fibers comprising the cervical vagusnerve to restore cardiac autonomic balance. Afferent action potentialspropagate toward the parasympathetic nervous system's origin in themedulla in the nucleus ambiguus, nucleus tractus solitarius, and thedorsal motor nucleus, as well as towards the sympathetic nervoussystem's origin in the intermediolateral cell column of the spinal cord.Efferent action potentials propagate toward the heart 17 to activate thecomponents of the heart's intrinsic nervous system. Either the left orright vagus nerve 15, 16 can be stimulated by the stimulation device 11.The right vagus nerve 16 has a moderately lower stimulation thresholdthan the left vagus nerve 15 for heart rate affects at the sameparametric levels.

The VNS therapy is delivered autonomously to the patient's vagus nerve15, 16 through three implanted components that include a neurostimulator12, therapy lead 13, and helical electrodes 14. FIGS. 2A and 2B arediagrams respectively showing the implantable neurostimulator 12 and thesimulation therapy lead 13 of FIG. 1. In one embodiment, theneurostimulator 12 can be adapted from a VNS Therapy AspireSR Model 106pulse generator, manufactured and sold by Cyberonics, Inc., Houston,Tex., although other manufactures and types of single-pin receptacleimplantable VNS neurostimulators with integrated leadless heart ratesensors could also be used. The stimulation therapy lead 13 and helicalelectrodes 14 are generally fabricated as a combined assembly and can beadapted from a Model 302 lead, PerenniaDURA Model 303 lead, orPerenniaFLEX Model 304 lead, also manufactured and sold by Cyberonics,Inc., in two sizes based on helical electrode inner diameter, althoughother manufactures and types of single-pin receptacle-compatible therapyleads and electrodes could also be used.

Referring first to FIG. 2A, the neurostimulator 12 provides multimodalvagal stimulation. In a maintenance mode, the neurostimulator 12 isparametrically programmed to deliver continuously-cycling, intermittentand periodic ON-OFF cycles of VNS are delivered that produce actionpotentials in the underlying nerves that propagate bi-directionally. Ina restorative mode, the neurostimulator 12 is parametrically programmedto deliver VNS tuned to prevent initiation of or disrupt tachyarrhythmiathrough continuously-cycling, intermittent and periodic ON-OFF cycles ofVNS delivered at higher intensity, which could be higher output current,higher duty cycle, higher frequency, longer pulse width, or acombination of the foregoing parameters, than the maintenance dose aredelivered in response to the onset or progression of tachyarrhythmias.In an enhanced mode, which is further described with reference to FIGS.6 and 7, the neurostimulator 12 is parametrically programmed to deliverthe VNS tuned to prevent initiation of or disrupt tachyarrhythmiaspecifically upon patient awakening through continuously-cycling,intermittent and periodic ON-OFF cycles of VNS is delivered at deliveredat a higher intensity than the maintenance mode, higher output current,higher duty cycle, higher frequency, longer pulse width, or acombination of the foregoing parameters.

The neurostimulator 12 includes an electrical pulse generator that istuned to restore autonomic balance by triggering action potentials thatpropagate both afferently and efferently within the vagus nerve 15, 16.The neurostimulator 12 is enclosed in a hermetically sealed housing 21constructed of a biocompatible, implantation-safe material, such astitanium. The housing 21 contains electronic circuitry 22 powered by aprimary battery 23, such as a lithium carbon monoflouride battery. Theelectronic circuitry 22 is implemented using complementary metal oxidesemiconductor integrated circuits that include a microprocessorcontroller that executes a control program according to storedstimulation parameters and timing cycles; a voltage regulator thatregulates system power; logic and control circuitry, including arecordable memory 29 within which the stimulation parameters are stored,that controls overall pulse generator function, receives and implementsprogramming commands from the external programmer, or other externalsource, collects and stores telemetry information, processes sensoryinput, and controls scheduled and sensory-based therapy outputs; atransceiver that remotely communicates with the external programmerusing radio frequency signals; an antenna, which receives programminginstructions and transmits the telemetry information to the externalprogrammer; and a reed switch 30 that provides remote access to theoperation of the neurostimulator 12 using an external programmer, asimple patient magnet, or an electromagnetic controller. The recordablememory 29 can include both volatile (dynamic) and persistent (static)forms of memory, such as firmware within which the stimulationparameters and timing cycles can be stored. Other electronic circuitryand components are possible.

Externally, the neurostimulator 12 includes a header 24 to securelyreceive and connect to the therapy lead 13. In one embodiment, theheader 24 encloses a receptacle 25 into which a single pin for thetherapy lead 13 can be received, although two or more receptacles couldalso be provided, along with the requisite additional electroniccircuitry 22. The header 24 internally includes a lead connector block(not shown) and a set of set screws 26.

The housing 21 can also contain a heart rate sensor 31 that iselectrically interfaced with the logic and control circuitry, whichreceives the patient's sensed heart rate as sensory inputs. The heartrate sensor 31 monitors heart rate using an ECG-type electrode. Throughthe electrode, the patient's heart beat can be sensed by detectingventricular depolarization. In a further embodiment, a plurality ofelectrodes can be used to sense voltage differentials between electrodepairs, which can undergo signal processing for cardiac physiologicalmeasures, for instance, detection of the P-wave, QRS complex, andT-wave. The heart rate sensor 31 provides the sensed heart rate to thecontrol and logic circuitry as sensory inputs that can be used tomonitor whether the patient 10 is awake or asleep, as further describedinfra with reference to FIG. 6 and determine the presence of possibletachyarrhythmias, particularly VT.

In a further embodiment, the housing 21 contains a minute ventilationsensor 32 that is electrically interfaced with the logic and controlcircuitry, which receives the patient's respiratory dynamics as sensoryinputs. The minute ventilation sensor 32, such as described in U.S. Pat.No. 7,092,757, issued Aug. 15, 2006, to Larson et al., the disclosure ofwhich is incorporated by reference, measures the patient's respiratoryrate and tidal volume, and calculates the patient's minute ventilationvolume. The minute ventilation sensor 32 provides the minute ventilationvolume to the control and logic circuitry as sensory inputs that can beused to determine whether the patient is awake.

In a still further embodiment, the housing 21 contains an accelerometer33 that is electrically interfaced with the logic and control circuitry,which receives the patient's physical movement as sensory inputs. Theminute ventilation sensor 32 may be combined into a blended sensor withat least one accelerometer 33. The accelerometer 33 contains thecircuitry and mechanical components necessary to measure acceleration ofthe patient's body along at least two axes, and may include multipleuniaxial accelerometers, a dual axial accelerometer, or a triaxialaccelerometer. By measuring the acceleration along multiple axes, theaccelerometer 33 provides sensory inputs that can be used to determinethe patient's posture and rate of movement and whether the patient hasfallen or awakened from sleep. In a further embodiment, theaccelerometer 33 can be located separately from the minute ventilationsensor 32, either on the interior or exterior of the housing 21.

The neurostimulator 12 is preferably interrogated prior to implantationand throughout the therapeutic period with a healthcareprovider-operable external programmer and programming wand (not shown)for checking proper operation, downloading recorded data, diagnosingproblems, and programming operational parameters, such as described incommonly-assigned U.S. Pat. Nos. 8,60,505 and 8,571,654, cited supra.Generally, use of the external programmer is restricted to healthcareproviders, while more limited manual control is provided to the patientthrough “magnet mode.” In one embodiment, the external programmerexecutes application software specifically designed to interrogate theneurostimulator 12. The programming computer interfaces to theprogramming wand through a standardized wired or wireless dataconnection. The programming wand can be adapted from a Model 201Programming Wand, manufactured and sold by Cyberonics, Inc. and theapplication software can be adapted from the Model 250 ProgrammingSoftware suite, licensed by Cyberonics, Inc. Other configurations andcombinations of external programmer, programming wand and applicationsoftware are possible.

The neurostimulator 12 delivers VNS under control of the electroniccircuitry 22. The stored stimulation parameters are programmable. Eachstimulation parameter can be independently programmed to define thecharacteristics of the cycles of therapeutic stimulation and inhibitionto ensure optimal stimulation for a patient 10. The programmablestimulation parameters include output current, signal frequency, pulsewidth, signal ON time, signal OFF time, magnet activation (for VNSspecifically triggered by “magnet mode”), and reset parameters. Otherprogrammable parameters are possible. In addition, sets or “profiles” ofpreselected stimulation parameters can be provided to physicians withthe external programmer and fine-tuned to a patient's physiologicalrequirements prior to being programmed into the neurostimulator 12, suchas described in commonly-assigned U.S. Pat. No. 8,630,709, entitled“Computer-Implemented System and Method for Selecting Therapy Profilesof Electrical Stimulation of Cervical Vagus Nerves for Treatment ofChronic Cardiac Dysfunction,” Ser. No. 13/314,138, filed on Dec. 7,2011, the disclosure of which is incorporated by reference.

Referring next to FIG. 2B, the therapy lead 13 delivers an electricalsignal from the neurostimulator 12 to the vagus nerve 15, 16 via thehelical electrodes 14. On a proximal end, the therapy lead 13 has a leadconnector 27 that transitions an insulated electrical lead body to ametal connector pin 28. During implantation, the connector pin 28 isguided through the receptacle 25 into the header 24 and securelyfastened in place using the set screws 26 to electrically couple thetherapy lead 13 to the neurostimulator 12. On a distal end, the therapylead 13 terminates with the helical electrode 14, which bifurcates intoa pair of anodic and cathodic electrodes 62 (as further described infrawith reference to FIG. 4). In one embodiment, the lead connector 27 ismanufactured using silicone and the connector pin 28 is made ofstainless steel, although other suitable materials could be used, aswell. The insulated lead body 13 utilizes a silicone-insulated alloyconductor material.

Preferably, the helical electrodes 14 are placed over the cervical vagusnerve 15, 16 at the location below where the superior and inferiorcardiac branches separate from the cervical vagus nerve. In alternativeembodiments, the helical electrodes may be placed at a location abovewhere one or both of the superior and inferior cardiac branches separatefrom the cervical vagus nerve. In one embodiment, the helical electrodes14 are positioned around the patient's vagus nerve oriented with the endof the helical electrodes 14 facing the patient's head. In an alternateembodiment, the helical electrodes 14 are positioned around thepatient's vagus nerve 15, 16 oriented with the end of the helicalelectrodes 14 facing the patient's heart 17. At the distal end, theinsulated electrical lead body 13 is bifurcated into a pair of leadbodies that are connected to a pair of electrodes proper. The polarityof the electrodes could be configured into a monopolar cathode, aproximal anode and a distal cathode, or a proximal cathode and a distalanode.

Therapeutically, the VNS is delivered as a multimodal set of therapeuticand event-based doses, which are system output behaviors that arepre-specified within the neurostimulator 12 through the storedstimulation parameters and timing cycles implemented in firmware andexecuted by the microprocessor controller. The therapeutic doses includea cardiac cycle-independent maintenance dose that includescontinuously-cycling, intermittent and periodic cycles of electricalstimulation during periods in which the pulse amplitude is greater than0 mA (“therapy ON”) and during periods in which the pulse amplitude is 0mA (“therapy OFF”). The therapeutic doses also include a restorativedose at a higher level of intensity than the maintenance dose, whichcould be higher output current, higher duty cycle, higher frequency,longer pulse width, or a combination of the foregoing parameters, inresponse to the presence of tachyarrhythmias. Finally, the therapeuticdoses also include an enhanced dose of VNS tuned to prevent initiationof or disrupt tachyarrhythmia upon awakening throughcontinuously-cycling, intermittent and periodic ON-OFF cycles of VNSdelivered at a higher intensity than the maintenance dose, which couldbe higher output current, higher duty cycle, higher frequency, longerpulse width, or a combination of the foregoing parameters, in responseto the presence of tachyarrhythmias upon the patient's 10 awakening.

The neurostimulator 12 can operate either with or without an integratedheart rate sensor (provided that patient physiology can be monitoredthrough some other type of sensing mechanism), such as respectivelydescribed in commonly-assigned U.S. Pat. No. 8,577,458, entitled“Implantable Device for Providing Electrical Stimulation of CervicalVagus Nerves for Treatment of Chronic Cardiac Dysfunction with LeadlessHeart Rate Monitoring,” Ser. No. 13/314,126, filed on Dec. 7, 2011, andU.S. patent application, entitled “Implantable Device for ProvidingElectrical Stimulation of Cervical Vagus Nerves for Treatment of ChronicCardiac Dysfunction,” Ser. No. 13/314,119, filed on Dec. 7, 2011,pending, the disclosures of which are hereby incorporated by referenceherein in their entirety. Additionally, where an integrated leadlessheart rate monitor is available, the neurostimulator 12 can provideautonomic cardiovascular drive evaluation and self-controlled titration,such as respectively described in commonly-assigned U.S. patentapplication, entitled “Implantable Device for Evaluating AutonomicCardiovascular Drive in a Patient Suffering from Chronic CardiacDysfunction,” Ser. No. 13/314,133, filed on Dec. 7, 2011, published asUS 2013/0158616 A1, pending, and U.S. patent application, entitled“Implantable Device for Providing Electrical Stimulation of CervicalVagus Nerves for Treatment of Chronic Cardiac Dysfunction with BoundedTitration,” Ser. No. 13/314,135, filed on Dec. 7, 2011, published as US2013/0158617 A1, pending, the disclosures of which are incorporated byreference. Finally, the neurostimulator 12 can be used to ameliorateheart rate increase and decrease tachyarrhythmic risk followingexercise, such as described in commonly-assigned U.S. patentapplication, entitled “Implantable Neurostimulator-Implemented Methodfor Enhancing Heart Failure Patient Awakening Through Vagus NerveStimulation,” Ser. No. 13/673,811, filed on Nov. 9, 2012, published asUS 2014/0135864 A1, pending, the disclosure of which is incorporated byreference.

Therapeutically, VNS is delivered during the period following awakeningindependent of cardiac cycle and in an enhanced dose having an intensitythat is insufficient to elicit side-effects, such as cardiacarrhythmias. The selection of duty cycle is a tradeoff among competingmedical considerations. FIG. 3 is a graph 40 showing, by way of example,the relationship between the targeted therapeutic efficacy 43 and theextent of potential side effects 44 resulting from use of theimplantable neurostimulator 12 of FIG. 1. The x-axis represents the dutycycle 41. The duty cycle is determined by dividing the stimulation ONtime by the sum of the ON and OFF times of the neurostimulator 12 duringa single ON-OFF cycle. However, the stimulation time may also need toinclude ramp-up time and ramp-down time, where the stimulation frequencyexceeds a minimum threshold (as further described infra with referenceto FIG. 5). The y-axis represents physiological response 42 to VNStherapy. The physiological response 42 can be expressed quantitativelyfor a given duty cycle 41 as a function of the targeted therapeuticefficacy 43 and the extent of potential side effects 44, as describedinfra. The maximum level of physiological response 42 (“max”) signifiesthe highest point of targeted therapeutic efficacy 43 or potential sideeffects 44.

Targeted therapeutic efficacy 43 and the extent of potential sideeffects 44 can be expressed as functions of duty cycle 41 andphysiological response 42. The targeted therapeutic efficacy 43represents the intended effectiveness of VNS in provoking a beneficialphysiological response for a given duty cycle and can be quantified byassigning values to the various acute and chronic factors thatcontribute to the physiological response 42 of the patient 10 due to thedelivery of therapeutic VNS. Acute factors that contribute to thetargeted therapeutic efficacy 43 include beneficial changes in heartrate variability and increased coronary flow, reduction in cardiacworkload through vasodilation, and improvement in left ventricularrelaxation. Chronic factors that contribute to the targeted therapeuticefficacy 43 include improved cardiovascular regulatory function, as wellas decreased negative cytokine production, increased baroreflexsensitivity, increased respiratory gas exchange efficiency, favorablegene expression, renin-angiotensin-aldosterone system down-regulation,anti-arrhythmic, anti-apoptotic, and ectopy-reducing anti-inflammatoryeffects. These contributing factors can be combined in any manner toexpress the relative level of targeted therapeutic efficacy 43,including weighting particular effects more heavily than others orapplying statistical or numeric functions based directly on or derivedfrom observed physiological changes. Empirically, targeted therapeuticefficacy 43 steeply increases beginning at around a 5% duty cycle, andlevels off in a plateau near the maximum level of physiological responseat around a 30% duty cycle. Thereafter, targeted therapeutic efficacy 43begins decreasing at around a 50% duty cycle and continues in a plateaunear a 25% physiological response through the maximum 100% duty cycle.

The intersection 45 of the targeted therapeutic efficacy 43 and theextent of potential side effects 44 represents one optimal duty cyclerange for VNS. FIG. 4 is a graph 50 showing, by way of example, theoptimal duty cycle range 53 based on the intersection 45 depicted inFIG. 3. The x-axis represents the duty cycle 51 as a percentage ofstimulation time over inhibition time. The y-axis represents therapeuticpoints 52 reached in operating the neurostimulator 12 at a given dutycycle 51. The optimal duty range 53 is a function 54 of the intersection44 of the targeted therapeutic efficacy 43 and the extent of potentialside effects 44. The therapeutic operating points 52 can be expressedquantitatively for a given duty cycle 51 as a function of the values ofthe targeted therapeutic efficacy 43 and the extent of potential sideeffects 44 at their point of intersection in the graph 40 of FIG. 3. Theoptimal therapeutic operating point 55 (“max”) signifies a tradeoff thatoccurs at the point of highest targeted therapeutic efficacy 43 in lightof lowest potential side effects 44 and that point will typically befound within the range of a 5% to 30% duty cycle 51. Other expressionsof duty cycles and related factors are possible.

Therapeutically and in the absence of patient physiology of possiblemedical concern, such as cardiac arrhythmias, or following the patient'sawakening from sleep, VNS is delivered in a low level maintenance dosethat uses alternating cycles of stimuli application (ON) and stimuliinhibition (OFF) that are tuned to activate both afferent and efferentpathways. Stimulation results in parasympathetic activation andsympathetic inhibition, both through centrally-mediated pathways andthrough efferent activation of preganglionic neurons and local circuitneurons. FIG. 5 is a timing diagram showing, by way of example, astimulation cycle and an inhibition cycle of VNS 60 as provided byimplantable neurostimulator 12 of FIG. 1. The stimulation parametersenable the electrical stimulation pulse output by the neurostimulator 12to be varied by both amplitude (output current 66) and duration (pulsewidth 64). The number of output pulses delivered per second determinesthe signal frequency 63. In one embodiment, a pulse width in the rangeof 100 to 250 μsec delivers between 0.02 and 50 mA of output current ata signal frequency of about 20 Hz, although other therapeutic valuescould be used as appropriate.

In the simplest case, the stimulation time is the time period duringwhich the neurostimulator 12 is ON and delivering pulses of stimulation.The OFF time 65 is always the time period occurring in-betweenstimulation times 61 during which the neurostimulator 12 is OFF andinhibited from delivering stimulation. In one embodiment, theneurostimulator 12 implements a ramp-up time 67 and a ramp-down time 68that respectively precede and follow the ON time 62 during which theneurostimulator 12 is ON and delivering pulses of stimulation at thefull output current 66. The ramp-up time 67 and ramp-down time 68 areused when the stimulation frequency is at least 10 Hz, although otherminimum thresholds could be used, and both ramp-up and ramp-down times67, 68 last two seconds, although other time periods could also be used.The ramp-up time 67 and ramp-down time 68 allow the strength of theoutput current 66 of each output pulse to be gradually increased anddecreased, thereby avoiding deleterious reflex behavior due to suddendelivery or inhibition of stimulation at a programmed intensity.

The triggering of CHF compensatory mechanisms underlying a CCD increasesthe risk of tachyarrhythmias. In the hours following awakening, the riskof tachyarrhythmia is even higher. Although delivered in an enhanceddose upon patient awakening and, in a further embodiment, in amaintenance dose while the patient is awake, with an intensity that isinsufficient to elicit side-effects, such as cardiac arrhythmias,therapeutic VNS can nevertheless potentially prevent formation ofpathological tachyarrhythmias or at least ameliorate their occurrenceduring awakening in some patients. Although VNS has been shown todecrease defibrillation threshold, VNS is unlikely to terminate VF inthe absence of defibrillation. VNS prolongs ventricular action potentialduration, so may be effective in terminating VT. In addition, the effectof VNS on the AV node may be beneficial in patients with AF by slowingconduction to the ventricles and controlling ventricular rate.

While therapeutic VNS maintenance dose delivery can be suspended uponthe occurrence of tachyarrhythmia and replaced with the delivery of ahigher intensity VNS restorative dose that is tuned to preventinitiation of or disrupt tachyarrhythmia, neither of the doses areappropriate for the increased period of risk that a patient experiencesupon waking up. The maintenance dose may be too low to prevent theoccurrence of tachyarrhythmia during the diurnal peak, while therestorative dose may subject the patient to a high dose of VNSneedlessly on occasions that a tachyarrhythmic event does not occur.FIG. 6 is a flow diagram showing an implantableneurostimulator-implemented method for managing tachyarrhythmias uponthe patient's 10 awakening through vagus nerve stimulation 70, inaccordance with one embodiment. The method 70 is implemented on thestimulation device 11, the operation of which is parametrically definedthrough stored stimulation parameters and timing cycles. The method 70can be used for treatment of both CHF and non-CHF patients sufferingfrom other forms of chronic cardiac dysfunction.

Preliminarily, an implantable neurostimulator 12 with an integratedheart rate sensor 31, which includes a pulse generator 11, a nervestimulation therapy lead 13, and a pair of helical electrodes 14, isprovided (step 71). In an alternative embodiment, electrodes may beimplanted with no implanted neurostimulator or leads. Power may beprovided to the electrodes from an external power source andneurostimulator through wireless RF or inductive coupling. Such anembodiment may result in less surgical time and trauma to the patient.In a further embodiment, the integrated heart rate sensor 31 could beomitted in lieu of other types of sensing mechanisms for measuring thepatient's physiology.

The pulse generator stores a set of one or more operating modes (step72) that parametrically defines a low level maintenance dose, anenhanced dose, and a restorative dose of VNS stimulation, the latter twoof which are higher in intensity than the maintenance dose, as furtherdescribed infra with reference to FIG. 8. A sleeping patient's 10physiological state is regularly monitored to determine whether thepatient 10 has awakened from sleep (step 73). In a further embodiment,the risk of cardiac arrhythmias during or attendant to sleep,particularly sleep apneic episodes, can be managed by the implantableneurostimulator 12, such as described in commonly-assigned U.S. patentapplication, entitled “Implantable Neurostimulator-Implemented MethodFor Managing Tachyarrhythmic Risk During Sleep Through Vagus NerveStimulation,” Ser. No. 13/828,486, filed Mar. 14, 2013, published as US2014/0277232 A1, pending, the disclosure of which is incorporated byreference. In one embodiment, heart rate is used to check the patient'sphysiology using the heart rate sensor 31. A normative heart rate duringsleep is generally considered to fall between 60 to 70 beats per minute(bpm). Upon awakening, the heart rate naturally rises to an awake rangegenerally somewhere under 100 bpm, depending upon patient condition. Thenormative heart rate of the patient 10 is monitored and recordedperiodically while asleep to determine whether the patient 10 isawakening.

In general, awakening is characterized by the gradual onset of anincreased heart rate, which can be sensed by the neurostimulator 12, aswell as by evaluation of rhythm stability or related rate and rhythmmorphological indicators, such as conventionally used in cardiac rhythmmanagement devices. If the heart rate of the patient 10 is graduallyelevated above the mean normative heart rate level recorded duringsleep, for instance, a heart rate that gradually increases over aseven-minute period and is then maintained for a non-transitory periodof time, the patient 10 is considered to be awakening. In contrast,abrupt onset of increased heart rate could be indicative of a non-sinustachyarrhythmia.

In a still further embodiment, a minute ventilation sensor 32 can beused to determine patient awakening. Minute ventilation is closely tiedto heart rate during sleep, as ventilatory volume (tidal volume) andbreathing frequency (respiratory rate) decrease synchronously, as doesheart rate, as the patient falls asleep, then settles into a regularpattern. Tidal volume at rest is measured by the minute ventilationsensor 32. In general, tidal volume at rest is around 0.5 L/min and canincrease up to 3 L/min at a higher intensity level of exertion.Similarly, respiratory rate at rest is measured by the minuteventilation 32. In general, respiratory rate at rest is around 12 to 16breathes/min and can increase 40 to 50 breathes/min during maximumlevels of activity. A normative activity level while asleep isestablished by determining means of the tidal volume and respiratoryrate. If tidal volume and respiratory rate of the patient 10respectively exceed the mean resting values of tidal volume andrespiratory rate, the patient 10 is considered to be awakening. In astill further embodiment, the heart rate sensor 31 and the accelerometer32 can be used in combination with the minute ventilation sensor 32.Still other measures and indications of awakening are possible.

In a still further embodiment, the neurostimulator 12 can use a multipleforms of sensory data in determining whether the patient 10 hasawakened. As well, the neurostimulator 12 can assign more weight to onetype of sensory data over other types of sensory data. For example, moreweight can be assigned to accelerometer 33 data, which would discount arise in heart rate that occurs while the patient 10 remains recumbentand otherwise still. Other ways of preferentially weighting the data arepossible.

If the physiological state indicates that the patient 10 has notawakened from sleep (step 74), the patient's state is checked againperiodically. If the monitored physiological state is indicative of thepatient 10 having awakened (step 74), therapeutic VNS, as parametricallydefined by the enhanced dose operating mode, is delivered to at leastone of the vagus nerves through continuously-cycling, intermittent andperiodic electrical pulses to tuned to prevent initiation of or disrupttachyarrhythmia upon the patient's awakening (step 75), as furtherdescribed infra with reference to FIG. 7.

Following a completion of the enhanced dose delivery (step 75), a set ofoptional follow-up stimulation doses can be delivered as follows. Thepatient's normative physiology is monitored (step 76). If a conditionindicative of tachyarrhythmia is present (step 77), a restorative doseof VNS stimulation is initiated (step 78), such as further described inthe commonly-assigned U.S. patent application, entitled “ImplantableNeurostimulator-Implemented Method for Managing Tachyarrhythmia ThroughVagus Nerve Stimulation,” Ser. No. 13/673,766, filed Nov. 9, 2012,published as US 2014/0135862 A1, pending, the disclosure of which isincorporated by reference. Contrarily, in the absence oftachyarrhythmia, the presence of bradyarrhythmia is assessed (step 79).If a condition indicative of bradyarrhythmia is detected (step 79), themethod 70 is terminated and the bradyarrhythmia is addressed, such asdescribed in commonly-assigned U.S. Pat. No. 8,688,212, entitled“Implantable Neurostimulator-Implemented Method for Managing Bradycardiathrough Vagus Nerve Stimulation,” Ser. No. 13/554,656, filed on Jul. 20,2012, the disclosure of which is incorporated by reference. If acondition indicative of a bradyarrhythmia is absent (step 79), amaintenance dose of VNS stimulation is initiated (step 80), such asfurther described in the commonly-assigned U.S. patent application,entitled “Implantable Neurostimulator-Implemented Method for ManagingTachyarrhythmia Through Vagus Nerve Stimulation,” Ser. No. 13/673,766,filed Nov. 9, 2012, published as US 2014/0135862 A1, pending, thedisclosure of which is incorporated by reference.

The enhanced dose of VNS stimulation helps ameliorate tachyarrhythmiavulnerability during awakening. FIG. 7 is a flow diagram showing theroutine 90 for providing an enhanced dose that is engaged upon thepatient's 10 awakening for use in the method 70 of FIG. 6. An enhanceddose, which has a higher intensity than the maintenance dose, istherapeutically delivered (step 91). In one embodiment, the enhanceddose is parametrically defined with a pulse width in the range of 250 to500 μsec, delivering between 1.0 and 1.5 mA of output current at asignal frequency in the range of 10 to 20 Hz. The duty cycle may changesignificantly from nominally 10% to temporarily 50% or 100%, althoughother therapeutic values could be used as appropriate.

The patient's 10 normative physiology is monitored during delivery ofthe enhanced dose (step 92). The enhanced dose ameliorates, but does notfully eliminate, the risk of tachyarrhythmias. In general, the onset orpresence of pathological tachyarrhythmia can be determined by heart rateor rhythm, as well as rhythm stability, onset characteristics, andsimilar rate and rhythm morphological indicators, as conventionallydetected in cardiac rhythm management devices, such as described in K.Ellenbogen et al., “Clinical Cardiac Pacing and Defibrillation,” Ch. 3,pp. 68-126 (2d ed. 2000), the disclosure of which is incorporated byreference. If a condition indicative of tachyarrhythmia is detected(step 93), the intensity of the enhanced dose is progressively increased(step 94) and delivered (step 95). The neurostimulator 12 checks whetherthe time period for the delivery of the enhanced dose has expired (step96), terminating the routine 90 upon the period's expiration. In oneembodiment, a fixed period of one to three hours is used, although thetime period can be adjusted by a physician. In a further embodiment, thetime period can be extended if a tachyarrhythmic condition occurs.

If the time period has not expired (step 96), the responsiveness of thetachyarrhythmia to the enhanced dose is assessed (step 97).Non-responsiveness to the delivery of VNS stimulation can occur duringcontinuing heart rate elevation, which can present as no appreciablechange in heart rate, insufficient heart rate decrease, ornon-transitory increase in heart rate. Depending on the patient's 10heart response trajectory, the intensity of the enhanced dose can beprogressively increased by the same or similar amount each cycle (step94-97), or, for life-threatening or paroxysmal arrhythmias, immediatelyincreased to a strongly enhanced dose of significantly higher intensity(step 94), due to the lack of time to ramp up the intensityprogressively. The amount by which the intensity of the enhanced dose isprogressively increased can also depend on the heart rate trajectory. Inone embodiment, the strongly enhanced dose delivery (step 94) maximizesthe VNS stimulation, delivering the maximum intensity of stimulationthat the neurostimulator 12 can produce.

If the tachyarrhythmia is responding to the enhanced dose delivery (step97), therapeutic delivery of the enhanced dose at default intensity isresumed (step 91) upon the termination of the tachyarrhythmia. In afurther embodiment, the intensity of the enhanced dose can be increasedcontinuously, independently of the heart response trajectory, for theduration of the period of time.

On the other hand, as the delivery of the enhanced dose is bothpreventative and precautionary, heart rate could decrease in response tothe enhanced dose delivery as an unintended side-effect. If a conditionindicative of bradyarrhythmia is detected (step 98), the enhanced dosedelivery is suspended (step 99), terminating the routine 90.

Finally, in the absence of tachyarrhythmia (step 93) or bradyarrhythmia(step 98), the neurostimulator 12 checks whether the time period fordelivery of the enhanced dose has expired (step 100), terminating theroutine 90 if the period has expired. Otherwise, enhanced dose deliverycontinues (step 91).

In a still further embodiment, delivery of the enhanced, as well as therestorative dose, can be manually triggered, increased, decreased, orsuspended by providing the neurostimulator 12 with amagnetically-actuated reed switch, such as described incommonly-assigned U.S. Pat. Nos. 8,600,505 and 8,571,654, cited supra.In addition, the delivery of the enhanced dose and the maintenance dosecan also be manually swapped. For instance, the switch can be used whenthe maintenance dose is tolerable to the patient 10, while the enhanceddose and the restorative dose are intolerable. Other uses of the switchare possible.

The recordable memory 29 in the electronic circuitry 22 of theneurostimulator 12 (shown in FIG. 2A) stores the stimulation parametersthat control the overall functionality of the pulse generator 11 inproviding VNS therapy. FIG. 8 is a flow diagram showing a routine 110for storing operating modes for use with the method 70 of FIG. 6. Threeoperating modes are stored, which include a maintenance dose of VNStuned to restore cardiac autonomic balance (step 111) throughcontinuously-cycling, intermittent and periodic electrical pulses; anenhanced dose of VNS tuned to prevent initiation of or disrupttachyarrhythmia upon awakening through continuously-cycling,intermittent and periodic ON-OFF cycles of VNS delivered at a higherintensity than the maintenance dose (step 112); and a restorative dosetuned to prevent initiation of or disrupt tachyarrhythmia (step 113)through periodic electrical pulses delivered at a higher intensity thanthe maintenance dose.

In one embodiment, the autonomic regulation therapy is provided in a lowlevel maintenance dose independent of cardiac cycle to activate bothparasympathetic afferent and efferent neuronal fibers in the vagus nervesimultaneously and a high level enhanced dose. In the maintenance dose,a pulse width in the range of 250 to 500 μsec delivering between 0.02and 1.0 mA of output current at a signal frequency in the range of 10 to20 Hz, and a duty cycle of 5 to 30%, although other therapeutic valuescould be used as appropriate.

Different enhanced doses can be provided to respond to differenttachyarrhythmic events. The enhanced dose settings arephysician-programmable. For a default enhanced dose, the stimulationparameters would be in the same range as the maintenance dose, but wouldbe moderately higher, with a pulse width again in the range of 250 to500 μsec delivering between 1.5 and 2.0 mA of output current at a signalfrequency in the range of 10 to 20 Hz. The duty cycle may changesignificantly from nominally 10% to temporarily 50% or 100%, althoughother therapeutic values could be used as appropriate. Fornon-life-threatening or non-paroxysmal tachyarrhythmias, the intensityof the enhanced dose is progressively increased over time by increasingoutput current, duty cycle, or frequency, lengthening pulse width, orthrough a combination of the foregoing parameters. Discretely-definedenhanced doses, each using different parameters sets, may be deliveredin the course of treating a single continuing tachyarrhythmic event,such as for life-threatening or paroxysmal arrhythmias that rapidlygenerate and require a significantly strongly enhanced dose with no rampup time.

In a further embodiment, the suspension and resumption of the enhanceddose, maintenance dose, or restorative dose can be titrated to graduallywithdraw or introduce their respective forms of VNS.

While the invention has been particularly shown and described asreferenced to the embodiments thereof, those skilled in the art willunderstand that the foregoing and other change in form and detail may bemade therein without departing from the spirit and scope.

What is claimed is:
 1. A vagus nerve neurostimulator for modulatingautonomic cardiovascular drive, comprising: a pulse generator, whereinthe pulse generator generates a pulsed electrical signal comprising: asignal ON time; a signal OFF time; an output current; a signalfrequency; a pulse width; and a duty cycle defined by dividing thesignal ON time by the sum of the signal ON time and signal OFF time; atherapy lead; an electrode communicatively coupled to the pulsegenerator via the therapy lead, wherein the pulse generator applies theelectrical signal to the electrode adapted for a vagus nerve topropagate action potentials in both afferent and efferent directionsalong the vagus nerve at an intensity that avoids acute physiologicalside effects; and a sleep monitor, wherein the sleep monitor uponsensing a change in sleep state indicative of awakening causes the pulsegenerator to increase an intensity of the electrical signal to deliveran enhanced pulsed electrical signal via the therapy lead and theelectrode.
 2. The vagus nerve neurostimulator according to claim 1,wherein the enhanced pulsed electrical signal frequency is approximately10 Hz.
 3. The vagus nerve neurostimulator according to claim 1, whereinthe sleep monitor monitors a patient's physiological state.
 4. The vagusnerve neurostimulator according to claim 1, wherein the sleep monitorfurther comprises a heart rate sensor.
 5. The vagus nerveneurostimulator according to claim 4, wherein the heart rate sensor:establishes a normative heart rate of a patient as a mean heart ratesensed during the sleep state; periodically sensing the patient's heartrate with the heart rate sensor; and confirming that the patient isawakening when the patient's heart rate gradually rises and is sustainedat an elevated heart rate above the normative heart rate by a thresholdamount.
 6. The vagus nerve neurostimulator according to claim 5, whereinthe heart rate monitor monitors the patient's normative physiologyduring the delivery of the enhanced pulsed electrical signal, and uponsensing a condition indicative of an onset of tachyarrhythmia, the vagusnerve neurostimulator delivers a second enhanced pulsed electricalsignal.
 7. The vagus nerve neurostimulator according to claim 6, whereinthe heart rate monitor monitors the patient's normative physiologyduring the delivery of the enhanced pulsed electrical signal, and uponsensing a condition indicative of an onset of tachyarrhythmia,intensifying the electrical therapeutic stimulation to deliver thesecond enhanced pulsed electrical signal.
 8. The vagus nerveneurostimulator according to claim 6, wherein second enhanced pulsedelectrical signal is different than the enhanced electrical signal. 9.The vagus nerve neurostimulator according to claim 1, wherein the sleepmonitor further comprises an accelerometer.
 10. The vagus nerveneurostimulator according to claim 9, wherein the sleep monitor:establishes a normative activity level of the patient with theaccelerometer as a mean frequency of movement sensed during the sleepstate; periodically sensing the patient's activity level with theaccelerometer; and confirming that the patient is awakening from thesleep state when the patient's activity level gradually rises and issustained at an elevated activity level above the normative activitylevel accompanied by an increased frequency of movement by a thresholdamount.
 11. The vagus nerve neurostimulator according to claim 1,wherein the sleep monitor further comprises a minute ventilation sensor.12. The vagus nerve neurostimulator according to claim 11, wherein sleepmonitor: establishes a normative tidal volume and normative respiratoryrate of the patient with the minute ventilation sensor sensed during thesleep state; periodically sensing the patient's tidal volume andrespiratory rate with the minute ventilation sensor; and confirming thatthe patient is awakening from the sleep state when the patient's tidalvolume and respiratory rate gradually rise and are sustained at elevatedlevels respectively above the normative tidal volume and the normativerespiratory rate by a threshold amount.
 13. The vagus nerveneurostimulator according to claim 1, wherein the pulsed electricalsignal further comprises a signal ramp-up time and a ramp-down time. 14.The vagus nerve neurostimulator according to claim 13, wherein theoutput current, the signal frequency or the pulse width of the pulsedelectrical signal is modified during the ramp-up time.
 15. The vagusnerve neurostimulator according to claim 13, wherein the output current,the signal frequency or the pulse width of the pulsed electrical signalis modified during the ramp-down time.
 16. The vagus nerveneurostimulator according to claim 1, wherein the duty cycle comprises avalue in a range of 5% to 20%.
 17. The vagus nerve neurostimulatoraccording to claim 1, wherein the sleep monitor upon sensing the changein sleep state indicative of awakening causes the pulse generator toincrease the intensity of the electrical signal by increasing afrequency of the electrical signal.
 18. The vagus nerve neurostimulatoraccording to claim 1, wherein the sleep monitor upon sensing the changein sleep state indicative of awakening causes the pulse generator toincrease the intensity of the electrical signal by increasing an outputcurrent of the electrical signal.
 19. The vagus nerve neurostimulatoraccording to claim 1, wherein the sleep monitor upon sensing the changein sleep state indicative of awakening causes the pulse generator toincrease the intensity of the electrical signal by increasing a dutycycle of the electrical signal.
 20. The vagus nerve neurostimulatoraccording to claim 1, wherein the sleep monitor upon sensing the changein sleep state indicative of awakening causes the pulse generator toincrease the intensity of the electrical signal by increasing a pulsewidth of the electrical signal.